One of the approaches against thrombosis is the inhibition of the enzyme activity towards thrombin. Recently, compounds having antagonistic effects on thrombin receptors are expected to exhibit excellent effects for the treatment and prevention of thrombin-related diseases such as thrombosis, vascular restenosis, deep phlebothrombosis, pulmonary embolism, cerebral infarction, cardiac diseases, disseminated intravascular coagulation syndrome, hypertension, inflammatory diseases, rheumatism, asthma, glomerulonephritis, osteoporosis, nerve disorders, malignant tumors, and so on. Accordingly, there was a need for thrombin receptor antagonists that satisfy points such as pharmacological activity, receptor specificity to thrombin receptors, safety, dose and oral usefulness.
The present inventors have already found that 2-iminopyrrolidine derivatives and their salts have excellent thrombin receptor-inhibitory activity, and are useful as thrombin receptor antagonists (Patent Document 1: WO02/085855). Among the 2-iminopyrrolidine derivatives and their salts disclosed in Patent Document 1, methods for producing 1-(3-tert-butyl-4-methoxy-5-morpholino-phenyl)-2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-2-isoindol-2-yl)-ethanone (hereinafter may be referred to as “cyclic benzamidine derivative (C)”) represented by formula (XIII),
or a salt thereof, are described in Patent Document 1.
More specifically, as an example of methods for producing the cyclic benzamidine derivative (C) in the presence of N,N-dimethylformamide (DMF) as a solvent, Patent Document 1 discloses the method of coupling 5,6-diethoxy-7-fluoro-3H-isoindol-1-ylamine represented by the following formula:
or 5,6-diethoxy-7-fluoro-1,2-dihydroisoindol-1-ylimine represented by
(hereinafter, these compounds may be referred to as “fluorinated cyclic benzamidine derivative (A)”),and 2-bromo-1-(3-tert-butyl-4-methoxy-5-morpholinophenyl)ethanone represented by the following formula:
(hereinafter, it may be referred to as “morpholine-substituted phenacyl derivative (B)).
A method of producing the fluorinated cyclic benzamidine derivative (A) is described as dissolving 4,5-diethoxy-3-fluorophthalonitrile, which is represented by the following formula, in ethylacetate-ethanol-methanol, and adding platinum oxide.
However, this method has a low yield of the desired compound, leads to formation of numerous by-products, and requires purification immediately after the reaction due to product instability. Furthermore, since the products have high adsorptivity for the platinum catalyst, treatments to avoid hazardous ignition from the remaining platinum catalyst are necessary even after catalyst filtration, thus posing complicated purification issues. Patent Document 1 uses a known compound 1,2-diethoxy-3-fluorobenzene as the raw material for producing a fluorinated cyclic benzamidine derivative (A), but its low overall yield was a problem.
Therefore, methods of producing the fluorinated cyclic benzamidine derivative (A), or a salt thereof, that give high overall yields, have easy reaction procedures, and are useful even in an industrial scale production were anticipated.
Patent Document 1 discloses a method of producing the morpholine-substituted phenacyl derivative (B) using 2-tert-butylphenyl as the raw material. However, this method has problems such as: the necessity to include manipulations to secure safety since a nitro compound is used in the reaction procedure; the need to use expensive reagents such as 2-bromoethylether; and low overall yield.
Therefore, economical and industrially advantageous methods for producing the morpholine-substituted phenacyl derivative (B) or a salt thereof, which have simple reaction procedures and give high overall yields were required.
Furthermore, the reaction of coupling the fluorinated cyclic benzamidine derivative (A) or a salt thereof with the morpholine-substituted phenacyl derivative (B) to obtain the cyclic benzamidine derivative (C) or a salt thereof also had complicated purification procedure issues.
Therefore, there was a need for overall industrially advantageous methods for producing the cyclic benzamidine derivative (C), or a salt thereof, including methods of synthesizing raw materials such as the aforementioned compound (A) and compound (B).